One of the main goals in the study of hypertrophy is to elucidate the factors and pathways responsible for the development and maintenance of adaptive responses and distinguish them, if possible, from those responsible for the potentially pathological changes. Importantly, the upregulation or, in some cases, down-regulation of genes, several of which are normally expressed in the embryonic heart, is associated with distinct pathophysiological phenotypes in the hypertrophying and failing heart. One of these genes, the Na+-Ca2+ exchanger is upregulated at the transcriptional level in cardiac hypertrophy, ischemia and failure. Relatively little is known concerning which transcription factors and pathways are required for the induction and maintenance of the hypertrophic response. Using an adenoviral gene delivery system, we have shown that integrin activation is sufficient for the upregulation of the exchanger gene in adult cardiocytes. Preliminary data support that this is via a FAK-independent pathway which includes PKC, Ras and ERK1/2. In addition, we propose that integrin and alpha-adrenergic stimulation of NCX1 expression may also be via activated JNK. Our central hypothesis is that: Integrins are in part responsible for coupling the changes in hemodynamic load into bio-chemical signaling pathways which regulate some of the changes in cardiac gene expression, including that of the Na+-Ca2+ exchanger. We propose the following Specific Aims to test this hypothesis and characterize the signal transduction pathways, transcription factors and cis elements which mediate integrin induced NCX1 upregulation. 1) Identification of the signaling factors in the FAK-independent, integrin-mediated ERK1/2 pathway. 2) Identification of the factors mediating MAPK-stimulated upregulation of the Na+-Ca2+ exchanger gene. 3) Test the role of JNK in the upregulation of the Na+-Ca2+ exchanger gene. This work would provide a launching point to directly examine the co- ordinate regulation of genes in cardiac hypertrophy. Connecting the genes to the molecular pathways that initiate, promote and suppress their expression will allow for the identification of potential therapeutic targets. The therapeutic modulation of these targets may potentially reverse the endpoints associated with the disease phenotype.